Novel compounds

ABSTRACT

This invention relates to compounds of formula I 
     
       
         
         
             
             
         
       
     
     their use as positive allosteric modulators of mGlu5 receptor activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of neurological and psychiatric disorders associated with glutamate dysfunction such as schizophrenia or cognitive decline such as dementia or cognitive impairment. A, B, Ar, R 1 , R 2 , R 3 , R 3a  have meanings given in the description.

FIELD OF THE INVENTION

This invention relates to substituted imidazoles and their use as positive allosteric modulators of mGlu5 receptor activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of neurological and psychiatric disorders associated with glutamate dysfunction such as schizophrenia or cognitive decline such as dementia or cognitive impairment.

BACKGROUND OF THE INVENTION

Glutamate is the primary excitatory amino acid in the mammalian central nervous system. Neurotransmission mediated by glutamate has been demonstrated to be critical in many physiological processes, such as synaptic plasticity, long term potentiation involved in both learning and memory as well as sensory perception (Riedel et al., Behav. Brain Res. 2003, 140:1-47). Furthermore, it has been demonstrated that an imbalance of glutamate neurotransmission plays a critical role in the pathophysiology of various neurological and psychiatric diseases.

The excitatory neurotransmission of glutamate is mediated through at least two different classes of receptors, the ionotropic glutamate receptors (NMDA, AMPA and kainate) and the metabotropic glutamate receptors (mGluR). The ionotropic receptors are ligand gated ion channels and are thought to be responsible for the regulating rapid neuronal transmission between two neurons. The metabotropic glutamate receptors are G-protein coupled receptors (GPCRs) which appear to mediate not only synaptic transmission, but also to regulate the extent of neurotransmitter release as well as post synaptic receptor activation. Dysregulation in glutamatergic neurotransmission, for example through altered glutamate release or post-synaptic receptor activation, has been demonstrated in a variety of neurological ans well as psychiatric disorders. Hypofunction of the NMDA receptor has not only been demonstrated in Alzheimer's patients, but is increasingly accepted as the putative cause of schizophrenia (Farber et al., Prog. Brain Res., 1998, 116: 421-437, Coyle et al., Cell. and Mol. Neurobiol. 2006, 26: 365-384). This is supported by clinical studies showing that antagonists of the NMDA receptor induce symptoms indistinguishable to those suffered by schizophrenia patients (Javitt et al., Am J. Psychiatry, 1991, 148: 1301-1308). Therefore, approaches that could potentiate or normalize NMDA receptor signaling have the potential to treat neurological and psychiatric disorders. mGluR5 belongs to a superfamily of currently eight identified Type III GPCRs, which are unique in that the glutamate ligand binds to a large extracelullar amino-terminal protein domain. This superfamily is further divided into three gropus (Group I, II and III) based on amino acid homology as well as the intracellular signalling cascades they regulate (Schoepp et al., Neuropharma, 1999, 38:1431-1476). mGluR5 belongs to group I and is coupled to the phospholipase C signalling cascade which regulates intracellular calcium mobilization.

In the CNS, mGluR5 has been demonstrated to be expressed mainly in the cortex, hippocampus, nucleus accumbens and the caudate-putamen. These brain regions are known to be involved in memory formation and cogntive function as well as emotional response. mGluR5 has been shown to be localized post-synaptically, adjacent to the post-synaptic density (Luj an et al., Eur. J. Neurosci. 1996, 8: 1488-1500). A functional interaction between mGluR5 and the NMDA receptor has also been demonstrated, where activation of mGluR5 potentiates the activation state of the NMDA receptor (Mannaioni et al, NeuroSci., 2001, 21:5925-5924, Rosenbrock et al., Eur. J. Pharma., 2010, 639:40-46). Furthermore, activation of mGluR5 has been demonstrated in pre-clinical in vivo models to rescue cognitive impairment as well as psychotic disturbance induced by NMDA receptor antagonists (Chan et al., Psychopharma. 2008, 198:141-148). Therefore, activation of mGluR5, and thereby potentiation or normalization of the NMDA receptor signaling, is a potential mechanism for the treatment of psychiatric and neurological disorders.

Most agonists of mGluR5 bind the orthosteric glutamate binding site. Since the glutamate binding site between the mGluR family members is highly conserved, it has been challenging to develop selective mGluR5 agonists which have acceptable CNS penetration and demonstrate in vivo activity. An alternative approach to achieve selectivity between the mGluR family members is to develop compounds which bind to an allosteric site, which is not as highly conserved between the family members. These allosteric binding compounds would not interfere with the natural glutamate binding and signaling, but modulate the receptor activation state.

Positive allosteric modulators of mGluR5 have recently been identified (O'Brien et al., Mol. Pharma. 2003, 64: 731-740, Lindsley et al., J. Med. Chem. 2004, 47: 5825-5828). These compounds potentiate mGluR5 activity in the presence of bound glutamate. In the absence of bound glutamate, the mGluR5 positive modulators do not demonstrate intrinsic activity. Therefore, these compounds potentiate the natural signaling of mGluR5 as opposed to agonists which activate the receptor in a permanent, unnatural manner. mGluR5 positive allosteric modulators therefore represent an approach to potentiate mGluR5 signaling which in turn potentiates and normalizes the NMDA receptor hypofunction detected in neurological and psychiatric disorders.

WO 2003/105853 and WO 2005/056015 disclose substituted pyrazoles that are said to be CCR1 receptor antagonists and to be useful for the treatment of inflammation and immune disorders. Quite surprisingly, according to the present invention, some selected imidazole derivatives show positive modulatory activity on the mGluR5 receptor without having an inhibitory effect on the CCR1 receptor. Such compounds are useful for the treatment of psychotic disorders, cognitive disorders and dementias.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of formula I:

in which

-   A and B independently represent CH or N; -   R¹ represents aryl, heteroaryl, C₁₋₈alkyl, C₃₋₇cycloalkyl,     —O—C₁₋₈alkyl which latter five groups are optionally substituted     with one or more substituents selected from halogen, —CN, C₁₋₃alkyl,     —O—C₁₋₃alkyl; -   R², R³, R^(3a) independently represent —H, halogen, —CN, C₁₋₅alkyl,     C₃₋₅cycloalkyl, —O—C₁₋₅alkyl which latter three groups are     optionally substituted with one or more fluorine atoms, or -   R³ and R^(3a) may together with the six-membered ring to which they     are connected form a tetrahydropyran or N-methyl imidazole ring; -   Ar represents

-   R⁴ and R⁵ independently represent —H, halogen, —OH, —CN, —NH₂,     C₁₋₅alkyl, phenyl, —NH—C₁₋₅alkyl, —N(C₁₋₅alkyl)₂, —O—C₁₋₅alkyl,     —COO—C₁₋₅alkyl, —CONH(C₁₋₅alkyl), —CON(C₁₋₅alkyl)₂,     —NHCONH—C₁₋₅alkyl, —NHCON(C₁₋₅alkyl)₂, —NHCO—C₁₋₅alkyl which latter     eleven groups are optionally substituted with one or more     substituents selected from halogen, —OH;     or a salt thereof, particularly a physiologically acceptable salt     thereof.

In a second embodiment, in the general formula I, A, B, Ar, R², R³, R^(3a) have the same meaning as defined in any of the preceding embodiments, and

-   R¹ represents phenyl, C₃₋₆cycloalkyl which latter two groups are     optionally substituted with one or more substituents selected from     fluoro, C₁₋₃alkyl.

In another embodiment, in the general formula I, A, B, R¹, R², R³, R^(3a) have the same meaning as defined in any of the preceding embodiments, and

-   Ar represents pyridinyl, pyridazinyl, pyrimidinyl, triazinyl,     purinyl which latter five groups are optionally substituted with one     or more substituents selected from fluoro, C₁₋₃alkyl, —O—C₁₋₃alkyl     which latter two groups are optionally substituted with one or more     fluorine atoms.

In another embodiment, in the general formula I, Ar, R¹ have the same meaning as defined in any of the preceding embodiments, and the group

represents phenyl, benzimidazolyl, 2,3-dihydrobenzopyranyl which latter three groups are optionally substituted with one or more substituents selected from chloro, fluoro, C₁₋₃alkyl, —O—C₁₋₃alkyl, which latter two groups are optionally substituted with one or more fluorine atoms.

A further embodiment of the present invention comprises compounds of formula I in which

-   R¹ represents phenyl, C₃₋₆cycloalkyl which latter two groups are     optionally substituted with one or more substituents selected from     fluoro, C₁₋₃alkyl; -   Ar represents pyridinyl, pyridazinyl, pyrimidinyl, triazinyl,     purinyl which latter five groups are optionally substituted with one     or more substituents selected from fluoro, C₁₋₃alkyl, O—C₁₋₃alkyl     which latter two groups are optionally substituted with one or more     fluorine atoms;     the group

represents phenyl, benzimidazolyl, 2,3-dihydrobenzopyranyl which latter three groups are optionally substituted with one or more substituents selected from chloro, fluoro, C₁₋₃alkyl, —O—C₁₋₃alkyl, which latter two groups are optionally substituted with one or more fluorine atoms; or a salt thereof, particularly a physiologically acceptable salt thereof.

In another embodiment, in the general formula I, A, B, R¹, R², R³, R^(3a) have the same meaning as defined in any of the preceding embodiments, and

-   Ar represents phenyl,

-   -   which latter eight groups are optionally substituted with one or         more substituents selected from fluoro, C₁₋₃alkyl, O—C₁₋₃alkyl         which latter two groups are optionally substituted with one or         more fluorine atoms.

In another embodiment, in the general formula I, Ar, R¹ have the same meaning as defined in any of the preceding embodiments, and

-   A represents N or CH; -   B represents CH.

In another embodiment, in the general formula I, Ar, R¹ have the same meaning as defined in any of the preceding embodiments, and

-   A and B represent CH.

In another embodiment, in the general formula I, A, B, Ar, R², R³, R^(3a) have the same meaning as defined in any of the preceding embodiments, and

-   R¹ represents phenyl, cyclohexyl,

In another embodiment, in the general formula I, A, B, R¹, R², R³, R^(3a) have the same meaning as defined in any of the preceding embodiments, and

-   Ar represents

In another embodiment, in the general formula I, Ar, R¹ have the same meaning as defined in any of the preceding embodiments, and the group

represents

A further embodiment of the present invention comprises compounds of formula I in which

-   R¹ represents phenyl,

-   Ar represents

the group

represents

or a salt thereof, particularly a physiologically acceptable salt thereof.

TERMS AND DEFINITIONS USED General Definitions

Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.

In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, C₁₋₆-alkyl means an alkyl group or radical having 1 to 6 carbon atoms. In general, for groups comprising two or more subgroups, the last named subgroup is the radical attachment point, for example, the substituent “aryl-C₁₋₃-alkyl-” means an aryl group which is bound to a C₁₋₃-alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached.

In case a compound of the present invention is depicted in form of a chemical name and as a formula in case of any discrepancy the formula shall prevail.

An asterisk is may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.

The numeration of the atoms of a substituent starts with the atom which is closest to the core or to the group to which the substituent is attached.

For example, the term “3-carboxypropyl-group” represents the following substituent:

wherein the carboxy group is attached to the third carbon atom of the propyl group. The terms “1-methylpropyl-”, “2,2-dimethylpropyl-” or “cyclopropylmethyl-” group represent the following groups:

The asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.

Stereochemistry/Solvates/Hydrates:

Unless specifically indicated, throughout the specification and the appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers etc. . . . ) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.

Salts:

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. For example, such salts include salts from ammonia, L-arginine, betaine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine (2,2′-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol, 2-aminoethanol, ethylenediamine, N-ethyl-glucamine, hydrabamine, 1H-imidazole, lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine (2,2′,2″-nitrilotris(ethanol)), tromethamine, zinc hydroxide, acetic acid, 2.2-dichloro-acetic acid, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 2,5-dihydroxybenzoic acid, 4-acetamido-benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, decanoic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, ethylenediaminetetraacetic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycine, glycolic acid, hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, lysine, maleic acid, (−)-L-malic acid, malonic acid, DL-mandelic acid, methanesulfonic acid, galactaric acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, octanoic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionic acid, (−)-L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid. Further pharmaceutically acceptable salts can be formed with cations from metals like aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like. (also see Pharmaceutical salts, Berge, S. M. et al., J. Pharm. Sci., (1977), 66, 1-19).

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention (e.g. trifluoro acetate salts,) also comprise a part of the invention.

Halogen:

The term halogen generally denotes fluorine, chlorine, bromine and iodine.

Alkyl:

The term “C_(1-n)-alkyl”, wherein n is an integer from 2 to n, either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms. For example the term C₁₋₅-alkyl embraces the radicals H₃C—, H₃C—CH₂—, H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—, H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—, H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—, H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— and H₃C—CH₂—CH(CH₂CH₃)—.

Cycloalkyl:

The term “C_(3-n)-cycloalkyl”, wherein n is an integer from 4 to n, either alone or in combination with another radical denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms. For example the term C₃₋₇-cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Aryl:

The term “aryl” as used herein, either alone or in combination with another radical, denotes a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be further fused to a second 5- or 6-membered carbocyclic group which may be aromatic, saturated or unsaturated. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl.

Heteroaryl:

The term “heteroaryl” means a mono- or polycyclic-ring systems containing one or more heteroatoms selected from N, O or S(O)_(r), wherein r=0, 1 or 2, consisting of 5 to 14 ring atoms wherein at least one of the heteroatoms is part of aromatic ring. The term “heteroaryl” is intended to include all the possible isomeric forms.

Thus, the term “heteroaryl” includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:

Many of the terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another.

GENERAL METHOD OF PREPARATION

Compounds of the present invention can be prepared in accordance with techniques that are well known to those skilled in the art.

Compounds of the present invention can be synthesized according to scheme 1.

2-bromo-phenyl-ethanone derivates were reacted with several benzamidine derivates to give the desired 1H-imidazoles. 1H-imidazoles were coupled with methyl bromoacetate to the 1H-imidazoles-2yl esters, which were hydrolyzed with aqueous lithium hydroxide solution or aqueous sodium hydroxide solution. Finally, the 1H-imidazol-2-yl-acetic acid lithium salts were directly coupled with aryl substituted piperazines to the desired products.

A subseries of compounds can be synthesized according to scheme 2:

Methyl bromo acetate reacted with 2,4,5-tribromoimidazole to (2,4,5-tribromo-imidazol-1-yl)-acetic acid methyl ester. The ester was hydrolyzed with aqueous sodiumhydroxide solution to the corresponding acid. The acid was coupled with aryl piperazines under basic condition to the desired amids, followed by a Suzuki-reaction with different boronic acids. The resulting imidazol-1-yl-piperazin-ethanones were dehalogenated with butyllithium solution and subsequently coupled with different boronic acids to provide the desired products.

As an additional alternative, the compounds of this invention can be synthesized according to scheme 3:

The imidazole-derivatives were available commercially available or synthesized according to scheme 1. Coupling with bromo-arylpiperazinyl-ethanone derivates provided the desired products.

Biological Assay

The positive modulation of mGluR5 is measured in a HEK 293 cell line expressing human recombinant mGluR5 and is detected with calcium based FLIPR assay. The cells are cultured with DMEM supplemented with 10% FCS, 2 μg/mL tetracycline, 100 μg/mL hygromycin and 500 μg/mL gneticin. The cell culture media is exchanged for tetracycline-free cell culture media 3-7 days before the assay. One day before the assay the cell culture medium is exchanged to DMEM without glutamine and phenol red and supplemented with 10% FCS, 100 μg/mL hygromycin and 500 μg/mL geneticin. On the assay day, the medium of the subconfluent cultures is removed and the cells are detached by addition of 2.5 ml EDTA (0.02%) per 175 cm2 culture flask for 1 minute. The cells are resuspend in Ringer solution (140 mM NaCl, 5 mM KCl, 2.5 mM CaCl2, 1.5 mM MgCl2, 5 mM Glucose, 10 mM Hepes; adjusted to pH 7.4 with NaOH), pooled and Ringer solution added to adjust the volume to 50 mL. The cell suspension is centrifuged for 5 mM at 1500 U/min (425 g). The supernatant is removed and the cells washed a second time with 50 ml fresh Ringer solution and centrifuged again as before. The supernatant is again removed and the pellet resuspended in Ringer solution to 1,000,000 cells/ml (1×10̂6 cells/mL). The cells are plated onto BD BioCoat Poly-D-Lysine 384 well plates (20.000 cells/well; 20 μl/well). The lid covered plates are then incubated until use at 37° C./10% CO₂. For dye loading, 20 μl of Calcium-4 assay kit solution (prepared according to the manufacturer's description in Ringer solution) are added to the cells and the plates are incubated for 80 mM 37° C. and then 10 mM at room temperature.

Controls, Compound dilution and assay execution:

Each assay plate contained wells with “high” and “low” controls:

Low controls 1% DMSO/ringer solution+basal glutamate activation (defined as 100% CTL).

High controls 10 μM CDPPB+basal glutamate activation (defined as 200% CTL).

Test compounds are dissolved and diluted in DMSO to 100-fold the desired concentrations. In a second step, the compounds are diluted in Ringer solution such that the compounds are 4-fold more concentrated than the desired final assay concentration. The final DMSO concentration was 1%.

20 μl of each compound solution are then transferred to the assay plate and the Ca2+ kinetic is measured to determine any intrinsic compound activity. After 5 mM incubation in the FLIPR device, the second stimulation with 20 μl of glutamate in Ringer solution (glutamate concentration adjusted to approximately 5% basal stimulation of the maximal possible glutamate effect) is added and the kinetic Ca2+ response of the wells was measured for the modulation effect.

Analysis:

The peak height of the Ca release related fluorescence signal (9-66) is used for the EC50. The EC50 of the modulation is calculated over a nonlinear regression with GraphPad Prism (Table 1).

TABLE 1 EC50 EC50 EC50 EC50 Example [nM] Example [nM] Example [nM] Example [nM] 7.01.01. 1286 7.01.16. 877 7.01.31. 244 7.03.07. 38 7.01.02. 84 7.01.17. 542 7.01.32. 131 7.03.08. 151 7.01.03. 41 7.01.18. 99 7.01.33. 148 7.03.09. 48 7.01.04. 363 7.01.19. 31 7.01.34. 858 7.03.10. 159 7.01.05. 159 7.01.20. 73 7.01.35. 73 7.03.11. 914 7.01.06. 76 7.01.21. 53 7.01.36. 196 7.03.12. 29 7.01.07. 53 7.01.22. 144 7.02.01. 464 7.03.13. 158 7.01.08. 97 7.01.23. 75 7.02.02. 1642 7.03.14. 183 7.01.09. 1322 7.01.24. 147 7.02.03. 851 7.03.15. 61 7.01.10. 737 7.01.25. 69 7.03.01. 272 7.03.16. 1527 7.01.11. 710 7.01.26. 83 7.03.02. 67 7.03.17. 40 7.01.12. 458 7.01.27. 238 7.03.03. 54 7.03.18. 74 7.01.13. 857 7.01.28. 262 7.03.04. 395 7.01.14. 306 7.01.29. 889 7.03.05. 87 7.01.15. 858 7.01.30. 168 7.03.06. 680

Method of Treatment

The present invention is directed to compounds of general formula I which are useful in the treatment of a disease and/or condition wherein the activity of an mGluR5 positive modulator is of therapeutic benefit, including but not limited to the treatment of psychotic disorders, cognitive disorders and dementias.

The compounds of general formula I are useful for the treatment of psychotic disorders including schizophrenia, schizoaffective disorder and substance induced psychotic disorder; cognitive disorders and dementias including age-associated learning and memory impairments or losses, post stroke dementia, deficits in concentration, mild cognitive impairment, the cognitive dysfunction in Alzheimers disease, and the cognitive dysfunction of schizophrenia. Therefore, the present invention also relates to a compound of general formula I as a medicament.

A further aspect of the present invention relates to the use of a compound of general formula I for the treatment of a disease and/or condition wherein the activity of mGluR5 positive modulator is of therapeutic benefit.

Furthermore, the present invention relates to the use of a compound of general formula I for the treatment of psychotic disorders, cognitive disorders and dementias.

Furthermore, the present invention relates to the use of a compound of general formula I for the treatment of psychotic disorders including schizophrenia, schizoaffective disorder and substance induced psychotic disorder; cognitive disorders and dementias including age-associated learning and memory impairments or losses, post stroke dementia, deficits in concentration, mild cognitive impairment, the cognitive dysfunction in Alzheimers disease, and the cognitive dysfunction of schizophrenia.

In a further aspect of the present invention the present invention relates to methods for the treatment or prevention of above mentioned diseases and conditions, which method comprises the administration of an effective amount of a compound of general formula Ito a human being.

Dosage

The dose range of the compounds of general formula I applicable per day is usually from 0.1 to 5000 mg, preferably from 0.1 to 1000 mg, more preferably from 5 to 500 mg, most preferably, 10 or 100 mg. Each dosage unit may conveniently contain from 0.1 to 500 mg, preferably 10 to 100 mg.

The actual pharmaceutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the combination will be administered at dosages and in a manner which allows a pharmaceutically effective amount to be delivered based upon patient's unique condition.

Pharmaceutical Compositions

Suitable preparations for administering the compounds of formula will be apparent to those with ordinary skill in the art and include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injectables, inhalatives and powders etc. The content of the pharmaceutically active compound(s) should be in the range from 1 to 99 wt.-%, preferably 10 to 90 wt.-%, more preferably 20 to 70 wt.-%, of the composition as a whole. Suitable tablets may be obtained, for example, by mixing one or more compounds according to formula I with known excipients, for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants. The tablets may also consist of several layers. A further aspect of the invention is a pharmaceutical formulation including a compound of formula I in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

Combination Therapy

In another aspect the present invention relates to a combination therapy in which an active compound according to the present invention is administered together with another active compound. Accordingly, the invention also refers to pharmaceutical formulations that provide such a combination of active ingredients, whereby one of which is an active compound of the present invention. Such combinations may be fixed dose combinations (the active ingredients that are to be combined are subject of the same pharmaceutical formulation) or free dose combinations (active ingredients are in separate pharmaceutical formulations). Consequently, a further aspect of the present invention refers to a combination of each of the active compounds of the present invention, preferably at least one active compound according to the present invention, with another active compound for example selected from the group of antipsychotics such as haloperidol, clozapine, risperidone, quetiapine, aripripazole, and olanzapine; antidepressants such as selective serotonin re-uptake inhibitors and dual serotonin/noradrenaline re-uptake inhibitors; mood stabilizers such as lithium valproate and lamotrigine; beta-secretase inhibitors; gamma-secretase inhibitors; gamma-secretase modulators; amyloid aggregation inhibitors such as e.g. scyllo-inositol; directly or indirectly acting neuroprotective and/or disease-modifying substances; anti-oxidants, such as e.g. vitamin E, ginko biloba or ginkolide; anti-inflammatory substances, such as e.g. Cox inhibitors, NSAIDs additionally or exclusively having AB (Abeta) lowering properties; HMG-CoA reductase inhibitors, such as statins; acetylcholine esterase inhibitors, such as donepezil, rivastigmine, tacrine, galantamine; NMDA receptor antagonists such as e.g. memantine; AMPA receptor agonists; AMPA receptor positive modulators, AMPkines, glycine transporter 1 inhibitors; monoamine receptor reuptake inhibitors; substances modulating the concentration or release of neurotransmitters; substances inducing the secretion of growth hormone such as ibutamoren mesylate and capromorelin; CB-1 receptor antagonists or inverse agonists; antibiotics such as minocyclin or rifampicin; PDE1, PDE2, PDE4, PDE5, PDE9 or PDE10 inhibitors, GABAA receptor inverse agonists; GABAA alpha5 receptor inverse agonists; GABAA receptor antagonists; nicotinic receptor agonists or partial agonists or positive modulators; alpha4beta2 nicotinic receptor agonists or partial agonists or positive modulators; alpha7 nicotinic receptor agonists or partial agonists; histamine receptor H3 antagonists; 5-HT4 receptor agonists or partial agonists; 5-HT6 receptor antagonists; alpha2-adrenoreceptor antagonists, calcium antagonists; muscarinic receptor M1 agonists or partial agonists or positive modulators; muscarinic receptor M2 antagonists; muscarinic receptor M4 antagonists; muscarinic receptor M4 positive allosteric modulators; metabotropic glutamate receptor 5 positive allosteric modulators; metabotropic glutamate receptor 2 antagonists; metabotropic glutamate receptor 2/3 agonists; metabotropic glutamate receptor 2 positive allosteric modulators and other substances that modulate receptors or enzymes in a manner such that the efficacy and/or safety of the active compounds according to the invention is increased and/or unwanted side effects are reduced.

The active compounds according to the invention may also be used in combination with immunotherapies such as e.g. active immunisation with Abeta or parts thereof or passive immunisation with humanised anti-Abeta antibodies, nanobodies or antibody fragments for the treatment of the above mentioned diseases and conditions.

The active compounds according to the invention also may be combined with antipsychotics like haloperidol, flupentixol, fluspirilene, chlorprothixene, prothipendyl, levomepromazine, clozapine, olanzapine, quetiapine, risperidone, paliperidone, amisulpride, ziprasidone, aripiprazol, sulpiride, zotepine, sertindole, fluphenazine, perphenazine, perazine, promazine, chlorpromazine, levomepromazine, benperidol, bromperidol, pimozid, melperone, pipamperone, iloperidone, asenapine, perospirone, blonanserin, lurasidone.

The active compounds according to the invention also may be combined with antidepressants like amitriptyline imipramine hydrochloride, imipramine maleate, lofepramine, desipramine, doxepin, trimipramine.

Or the active compounds according to the invention also may be combined with serotonin (5-HT) reuptake inhibitors such as alaproclate, citalopram escitalopram, clomipramine, duloxetine, femoxetine, fenfluramine, norfenfluramine, fluoxetine, fluvoxamine, indalpine, milnacipran, paroxetine, sertraline, trazodone, venlafaxine, zimelidine, bicifadine, desvenlafaxine, brasofensme and tesofensine.

The combinations according to the present invention may be provided simultaneously in one and the same dosage form, i.e. in form of a combination preparation, for example the two components may be incorporated in one tablet, e.g. in different layers of said tablet. The combination may be also provided separately, in form of a free combination, i.e. the active compounds of the present invention are provided in one dosage form and one or more of the above mentioned combination partners is provided in another dosage form. These two dosage forms may be equal dosage forms, for example a co-administration of two tablets, one containing a therapeutically effective amount of the active compound of the present invention and one containing a therapeutically effective amount of the above mentioned combination partner. It is also possible to combine different administration forms, if desired. Any type of suitable administration forms may be provided.

The active compound according to the invention, or a physiologically acceptable salt thereof, in combination with another active substance may be used simultaneously or at staggered times, but particularly close together in time. If administered simultaneously, the two active substances are given to the patient together; if administered at staggered times the two active substances are given to the patient successively within a period of less than or equal to 12, particularly less than or equal to 6 hours.

The dosage or administration forms are not limited, in the frame of the present invention any suitable dosage form may be used. Exemplarily the dosage forms may be selected from solid preparations such as patches, tablets, capsules, pills, pellets, dragees, powders, troches, suppositories, liquid preparations such as solutions, suspensions, emulsions, drops, syrups, elixirs, or gaseous preparations such as aerosols, sprays and the like.

The dosage forms are advantageously formulated in dosage units, each dosage unit being adapted to supply a single dose of each active component being present. Depending from the administration route and dosage form the ingredients are selected accordingly.

The dosage for the above-mentioned combination partners may be expediently 1/5 of the normally recommended lowest dose up to 1/1 of the normally recommended dose.

The dosage forms are administered to the patient for example 1, 2, 3, or 4 times daily depending on the nature of the formulation. In case of retarding or extended release formulations or other pharmaceutical formulations, the same may be applied differently (e.g. once weekly or monthly etc.). It is preferred that the active compounds of the invention be administered either three or fewer times, more preferably once or twice daily.

EXPERIMENTAL SECTION Preparation of Examples for Compounds of the General Formula I

Unless otherwise stated, one or more tautomeric forms of compounds of the examples described hereinafter may be prepared in situ and/or isolated. All tautomeric forms of compounds of the examples described hereinafter should be considered to be disclosed.

The invention is illustrated by way of the following examples, in which the following abbreviations may be employed:

ABBREVIATIONS

-   RT: room temperature -   THF: tetrahydrofuran -   ACN: acetonitrile -   MeOH: methanol -   DIPEA: diisopropylamine -   DEA: diethylamine -   EtOAC: ethyl acetate -   DMF: dimethylformamide -   DCM: dichlormethane -   TBTU:     [(Benzotriazol-1-yloxy)-dimethylamino-methylene]-dimethyl-ammonium;     tetrafluoro borate -   conc.: concentrated -   min.: minutes -   DCM: dichlormethane -   HCl: hydrochlorid acid -   NMP: N-methyl-2-pyrrolidinone -   TEA: trietylamine -   Tetrakis tetrakis (triphenylphosphine) palladium(0)

Analytical Methods

All compounds specified in the examples below gave the correct mass spectra matching the theoretical isotope pattern. For practical reasons, only one of the major isotope peaks is given as representative data for the mass spectrum.

List of Analytical HPLC-Methods: Method A:

Agilent 1200 System

Eluent:

A: water with 0.10% formicacid

B: acetonitril 0.10% formicacid

Gradient:

time in flow in min % A % B ml/min 0.00 95 5 1.60 0.10 95 5 1.60 1.75 5 95 1.60 1.90 5 95 1.60 1.95 95 5 1.60 2.00 95 5 1.60

column: Zorbax StableBond C18, 3.0×30 mm, 1.8 μm (temperature: isocratic 20° C.).

detection: 254 nm

Method B:

Agilent 1200 System with diodenarraydetector and massdetector

Eluent:

A: water with 0.20% TFA

B: methanol

Gradient:

time in flow in min % A % B ml/min 0.00 95 5 2.20 0.05 95 5 2.20 1.40 0 100 2.20 1.80 0 100 2.20

column: Xbridge C18, 3.0×30 mm, 2.5 μm (temperature: isocratic 60° C.).

Method C:

Waters ZQ 2000MS, Agilent HP100, binare pumps

Eluent:

A: water with 0.1% TFA

B: methanol

Gradient:

time in flow in min % A % B ml/min 0.00 95 5 1.50 1.30 0 100 1.50 2.50 0 100 1.50 2.60 95 5 1.50

column: Sunfire C18, 4.6×50 mm, 3.5 μm (temperature: isocratic 40° C.).

diodenarray detection: 210-500 nm

Method D:

Waters ZQ 2000MS, Agilent HP100, binare pumps

Eluent:

A: water with 0.1% TFA

B: methanol

Gradient:

time in flow in min % A % B ml/min 0.00 95 5 1.50 1.30 0 100 1.50 3.00 0 100 1.50 3.40 95 5 1.50

column: Sunfire C18, 4.6×50 mm, 3.5 μm (temperature: isocratic 40° C.).

diodenarray detection: 210-500 nm

Method E:

Waters Acquity with diodenarraydetector and massdetector

Eluent:

A: water with 0.1% TFA

B: methanol

Gradient:

time in flow in min % A % B ml/min 0.00 99 1 1.50 0.05 99 1 1.50 1.05 0 100 1.50 1.20 0 100 1.50

column: Xbridge BEH C18, 2.1×30 mm, 1.7 μm (temperature: isocratic 60° C.).

diodenarray detektion: 210-400 nm.

Method F:

Waters Alliance with diodenarraydetector and massdetector

Eluent:

A: water with 0.10% TFA

B: methanol

Gradient:

time in flow in min % A % B ml/min 0.00 95 5 4.90 1.60 0 100 4.90 2.20 95 5 4.90

column: XBridge C18, 4.6×30 mm, 3.5 μm (temperature: isocratic 60° C.).

Method G:

Agilent 1200 System with diodenarraydetector and massdetector

Eluent:

A: water with 0.10% TFA

B: methanol

Gradient:

time in flow in min % A % B ml/min 0.00 95 5 2.20 0.30 95 5 2.20 1.50 0 100 2.20 1.50 0 100 2.90 1.65 0 100 2.90

column: Sunfire C18, 3.0×30 mm, 2.5 μm (temperature: isocratic 60° C.).

Method H:

Agilent 1100 System with diodenarraydetector and massdetector

Eluent:

A: water with 0.10% TFA

B: methanol with 0.10% TFA

Gradient:

time in flow in min % A % B ml/min 0.00 95 5 4.00 0.15 95 5 4.00 1.70 0 100 4.00 2.25 0 100 4.00

column: Xbridge C18, 4.6×30 mm, 3.5 μm (temperature: isocratic 60° C.).

Method I:

Agilent 1100 System with diodenarraydetector and massdetector

Eluent:

A: water with 0.10% TFA

B: methanol with 0.10% TFA

Gradient:

time in flow in min % A % B ml/min 0.00 95 5 4.00 0.15 95 5 4.00 1.70 0 100 4.00 2.25 0 100 4.00

column: Sunfire C18, 4.6×30 mm, 3.5 μm (temperature: isocratic 60° C.).

Method J:

Agilent 1200 System with diodenarraydetector and massdetector

Eluent:

A: water with 0.10% TFA

B: methanol

Gradient:

time in flow in min % A % B ml/min 0.00 95 5 2.20 0.30 95 5 2.20 1.50 0 100 2.20 1.50 0 100 2.90 1.65 0 100 2.90

column: Sunfire C18, 3.0×30 mm, 2.5 μm (temperature: isocratic 60° C.).

Method K:

Waters ZQ 2000MS, Agilent HP100, binare pumps

Eluent:

A: water with 0.1% ammonia

B: methanol

Gradient:

time in flow in min % A % B ml/min 0.00 80 20 2.00 1.70 0 100 2.00 2.50 0 100 2.00 2.60 80 5 2.00

column: Xbridge C18, 4.6×50 mm, 3.5 μm (temperature: isocratic 60° C.).

diodenarray detection: 210-500 nm

Method L:

Agilent 1200 System with diodenarraydetector and massdetector

Eluent:

A: water with 0.10% TFA

B: acetonitril

Gradient:

time in flow in min % A % B ml/min 0.00 95 5 2.20 0.05 95 5 2.20 1.40 0 100 2.20 1.80 0 100 2.20

column: Sunfire C18, 3.0×30 mm, 2.5 μm (temperature: isocratic 60° C.).

Synthesis of Intermediates 6.01. Synthesis of Building Blocks 6.01.01 2-bromo-1-(4-pyridin-2-yl-piperazin-1-yl)-ethanone

6.95 mL bromacetylbromide was dropped to 11.68 mL 1-pyridin-2-yl-piperazine and 11.23 mL triethylamine in 300 mL DCM at 0° C. The reaction was stirred 2 h at 0° C. The reaction mixture was added to water and extracted with DCM. The organic layer was dried with magesium sulfate and evaporated The residue was purified by chromatography on silica gel (DCM/MeOH 0-20%; 0.1% ammonia) to yield 23.6 g of the desired compound.

R_(t): 1.44 min (method D), (M+H)⁺: 284

6.01.02 5-methoxy-2-piperazin-1-yl-pyrimidine hydrochloride

6.01.02.01 4-(5-methoxy-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester

1.5 g piperazine-1-carboxylic acid tert-butyl ester was added to 1.2 g 2-chlor-5-methoxy-pyrimidine and 2.2 mL triethylamine in 30 mL DMF. The reaction was stirred 6 days at 60° C. The solvent was removed and the residue was dissolved in dichlormethane and extracted with water. The organic layer was washed with a saturated sodiumchloride-solution and evaporated. The residue was purified by HPLC to give 957 mg desired product.

R_(t): 0.82 min (method E), (M+H)⁺: 295

6.01.02.02 5-methoxy-2-piperazin-1-yl-pyrimidine hydrochloride

953 mg 4-(5-methoxy-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester was stirred in 16 mL 4 mol/L HCl solution in dioxane for 45 min The precipitate was filtered, washed with dioxane and dried to yield 723 mg of the desired compound.

R_(t): 0.46 min (method F), (M+H)⁺: 195

6.02. Synthesis of Imidazoles 6.02.01 2-bromo-1-(4-fluoro-3-methyl-phenyl)-ethanone

6.02.01.01 2-bromo-1-(4-fluoro-3-methyl-phenyl)-ethanone

0.67 mL bromine was added to 2 g 1-(4-fluoro-3-methyl-phenyl)-ethanone in 10 mL conc. acetic acid. The reaction was stirred for 3 h at RT and added to ice water. The precipitate was filtered, washed with water and dried to give 2.7 g desired product.

R_(t): 1.10 min (method B), (M+H)⁺: 231

By using the same synthesis strategy as for 2-bromo-1-(4-fluoro-3-methyl-phenyl)-ethanone the following compound was obtained:

MS m/z DC Example Product [M + H]⁺ Method 6.02.01.02

213 petrolether 95/ ethyl acetate 50.5

6.02.02 4-(4-fluoro-3-methyl-phenyl)-2-phenyl-1H-imidazole

6.02.02.01 4-(4-fluoro-3-methyl-phenyl)-2-phenyl-1H-imidazole

1.76 g potassium hydrogen carbonate in 15 mL water was added to 1.41 g benzamidine in 50 mL THF. The mixture was warmed up to 60° C. and 2.7 g 2-bromo-1-(4-fluoro-3-methyl-phenyl)-ethanone was added. The reaction was refluxed 5 h. The solvent was removed, water was added to the residue and the aqueous mixture extracted with ethyl acetate. The organic layer was dried and evaporated. The residue was purified by HPLC to give 2.3 g desired product.

R_(t): 0.96 min (method B), (M+H)⁺: 253

By using the same synthesis strategy as for 4-(4-fluoro-3-methyl-phenyl)-2-phenyl-1H-imidazole the following compounds were obtained:

MS HPLC Rt Examples Product m/z [M + H]⁺ Method min 6.02.02.02

259 method B 1.03 6.02.02.03

239 method B 1.08 6.02.02.04

271 method H 1.21 6.02.02.05

257 method B 0.90 6.02.02.06

235 method H 1.10

6.02.03 (4-(4-fluoro-3-methyl-phenyl)-2-phenyl-imidazol-1-yl)-acetic acid methyl ester

6.02.03.01 (4-(4-fluoro-3-methyl-phenyl)-2-phenyl-imidazol-1-yl)-acetic acid methyl ester

0.41 mL methyl bromoacetate was added to 1 g 4-(4-fluoro-3-methyl-phenyl)-2-phenyl-1H-imidazole and 1.66 g potassium carbonate in 10 mL DMF. The reaction was stirred 3 h at RT. Then 0.41 mL methyl bromoacetate was added and the reaction was stirred over night at RT. The reaction mixture was added to ice water and extracted with DCM. The organic layer was dried and evaporated to give 1 g desired product. R_(t): 0.94 min (method B), (M+H)⁺: 325

By using the same synthesis strategy as for (4-(4-fluoro-3-methyl-phenyl)-2-phenyl-imidazol-1-yl)-acetic acid methyl ester the following compounds were obtained:

MS HPLC Rt Examples Product m/z [M + H]⁺ Method min 6.02.03.02

311 method I 0.90 6.02.03.03

343 method H 1.18 6.02.03.04

329 method B 0.85 6.02.03.05

307 method H 1.10

6.02.04 (4-(4-fluoro-3-methyl-phenyl)-2-phenyl-imidazol-1-yl)-acetic acid

6.02.04.01 (4-(4-fluoro-3-methyl-phenyl)-2-phenyl-imidazol-1-yl)-acetic acid

A mixture of 220 mg lithiumhydroxide and 5 mL water was added to 1 g (4-(4-fluoro-3-methyl-phenyl)-2-phenyl-imidazol-1-yl)-acetic acid methyl ester in 15 mL THF. The reaction mixture was stirred overnight at RT and evaporated. Water was added to the residue and the mixture was acidified with 1 mol/L aqueous HCL solution. The precipitate was filtered and dried to give 540 mg desired product. R_(t): 0.86 min (method B), (M+H)⁺: 311

By using the same synthesis strategy as for (4-(4-fluoro-3-methyl-phenyl)-2-phenyl-imidazol-1-yl)-acetic acid the following compounds were obtained:

MS HPLC Rt Examples Product m/z [M + H]⁺ Method min 6.02.04.02

279 method A 0.87 6.02.04.03

297 method H 0.90 6.02.04.04

315 method B 0.70 6.02.04.05

293 method B 0.70

6.02.04.06 (4-(4-fluoro-3-methyl-phenyl)-2-(4-fluoro-phenyl)-imidazol-1-yl)-acetic acid

6.02.04.06 (4-(4-fluoro-3-methyl-phenyl)-2-(4-fluoro-phenyl)-imidazol-1-yl)-acetic acid

14 mL of a 1 mol/L aqueous sodiumhydroxide solution was added to 3.1 g (4-(4-fluoro-3-methyl-phenyl)-2-(4-fluoro-phenyl)-imidazol-1-yl)-acetic acid methyl ester in 50 mL MeOH. The reaction was stirred 3 h at RT and evaporated. Water was added to the residue and extracted with ethyl acetate. The aqueous layer was acidified with 1 mol/L aqueous HCL solution. The precipitate was filtered and dried to give 1.7 g desired product. R_(t): 1.07 min (method H), (M+H)⁺: 329

6.02.04.07 (2-cyclohexyl-4-(4-fluoro-3-methyl-phenyl)-imidazol-1-yl)-acetic acid

6.02.04.07 (2-cyclohexyl-4-(4-fluoro-3-methyl-phenyl)-imidazol-1-yl)-acetic acid

0.38 mL methyl bromoacetate was added to 940 mg 2-cyclohexyl-4-(4-fluoro-3-methyl-phenyl)-1H-imidazole and 1.52 g potassium carbonate in 10 mL DMF. The reaction was stirred over night at RT and evaporated. Methanol and 1 mol/L sodiumhydroxide solution was added and the mixture was stirred 2 h at RT. The solvent was removed. The residue was dissolved in water and acidified with 1 mol/L HCL solution. The precipitate was filtered and dried to give 700 mg desired product. R_(t): 0.92 min (method B), (M+H)⁺: 317

6.02.05 (2,4,5-tribromo-imidazol-1-yl)-acetic acid methyl ester

6.02.05.01 (2,4,5-tribromo-imidazol-1-yl)-acetic acid methyl ester

5.1 mL methyl bromo acetate was added to 15 g 2,4,5-tribromoimidazole and 20.4 g potassium carbonate in 100 mL DMF. The reaction was stirred 3 h at RT. The mixture was added to water. The precipitate was filtered, washed with water and dried to give 18.1 g desired product.

R_(t): 0.93 min (method B), ESI⁺: 375

6.02.06 (2,4,5-tribromo-imidazol-1-yl)-acetic acid

6.02.06.01 (2,4,5-tribromo-imidazol-1-yl)-acetic acid

18 mL 4 mol/L aqueous sodiumhydroxide solution was added to 18.1 g (2,4,5-tribromo-imidazol-1-yl)-acetic acid methyl ester in 200 mL MeOH. The reaction was stirred 1 h at RT and evaporated. Water was added to the residue and the resulting mixture acidified with 1 mol/L aqueous HCL solution. The precipitate was filtered and dried to give 17.2 g desired product.

R_(t): 0.80 min (method B), ESI⁺: 361

7.02.07 1-(4-pyrimidin-2-yl-piperazin-1-yl)-2-(2,4,5-tribromo-imidazol-1-yl)-ethanone

7.02.07.01 1-(4-pyrimidin-2-yl-piperazin-1-yl)-2-(2,4,5-tribromo-imidazol-1-yl)-ethanone

7.3 mL 2-piperazin-1-yl-pyrimidine was added to a mixture of 17 g (2,4,5-tribromo-imidazol-1-yl)-acetic acid, 16.6 g TBTU, 7.3 mL TEA and 100 mL DMF. The reaction mixture was stirred for 2 h at RT and subsequently added to water. The precipitate was filtered to give 23 g desired product. R_(t): 0.93 (method B), ESI⁺: 507

7.02.08 2-(4,5-dibromo-2-phenyl-imidazol-1-yl)-1-(4-pyrimidin-2-yl-piperazin-1-yl)-ethanone

7.02.08.01 2-(4,5-dibromo-2-phenyl-imidazol-1-yl)-1-(4-pyrimidin-2-yl-piperazin-1-yl)-ethanone

1.7 g tetrakis was added to a stirred mixture of 15 g 1-(4-pyrimidin-2-yl-piperazin-1-yl)-2-(2, 4, 5-tribromo-imidazol-1-yl)-ethanone, 3.6 g phenylboronic acid, 9.4 g sodiumcarbonate, 250 mL dioxane and 50 mL water under nitrogen atmosphere. The reaction mixture was stirred 3 h at 85° C. Sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. Diisopropylether was added to the residue and the precipitate was filtered to give 11.8 g desired product. R_(t): 0.87 (method B), ESI⁺: 505

7.02.09 2-(4-bromo-2-phenyl-imidazol-1-yl)-1-(4-pyrimidin-2-yl-piperazin-1-yl)-ethanone

7.02.09.01 2-(4-bromo-2-phenyl-imidazol-1-yl)-1-(4-pyrimidin-2-yl-piperazin-1-yl)-ethanone

9.4 mL 2.5 mol/L butyllithium solution in THF was added dropwise to 11.8 g 2-(4,5-dibromo-2-phenyl-imidazol-1-yl)-1-(4-pyrimidin-2-yl-piperazin-1-yl)-ethanone in 150 mL THF at −78° C. under argon. The reaction mixture was stirred 2 h at −78° C. followed by careful and dropwise addition of water to the mixture. The resulting mixture was stirred 30 min at −78° C. and then again water was added at 0° C. The mixture was extracted with ethyl acetate. The organic layer was dried and evaporated. The residue was purified chromatoraphie on silica (petrolether 1/ethylacetate 1). Diisopropylether was added to the residue and the precipitate was filtered and dried to give 1.7 g desired product. R_(t): 0.94 (method B), ESI⁺: 427

7. Synthesis of Target Compounds

7.01.01. 2-(2,4-Diphenyl-imidazol-1-yl)-1-(4-pyrimidin-2-yl-piperazin-1-yl)-ethanone

40 mg 2-piperazin-1-yl-pyrimidine was added to 70 mg (2,4-diphenyl-imidazol-1-yl)-acetic acid, 80 mg TBTU, 50 μL TEA in 1 mL DMF. The reaction was stirred overnight at RT. The mixture was purified by HPLC to give 50 mg desired product.

R_(t): 1.11 (method A) (M+H)⁺: 425

By using the same synthesis strategy as for 2-(2,4-Diphenyl-imidazol-1-yl)-1-(4-pyrimidin-2-yl-piperazin-1-yl)-ethanone the following compounds were obtained:

MS HPLC Rt Examples Product m/z [M + H]⁺ Method min 7.01.02

486 method B 0.86 7.01.03

457 method B 0.98 7.01.04

457 method B 0.81 7.01.05

487 method B 0.91 7.01.06

456 method B 0.82 7.01.07

487 method G 1.04 7.01.08

475 method G 1.05 7.01.09

493 method B 0.96 7.01.10

492 method B 0.87 7.01.11

462 method B 0.85 7.01.12

463 method B 1.05 7.01.13

503 method B 0.95 7.01.14

472 method B 0.73 7.01.15

483 method B 0.78 7.01.16

473 method B 0.80 7.01.17

442 method B 0.68 7.01.18

505 method J 0.76 7.01.19

475 method J 0.83 7.01.20

515 method J 0.71 7.01.21

475 method J 0.84 7.01.22

475 method J 0.67 7.01.23

504 method J 0.71 7.01.24

476 method J 0.74 7.01.25

505 method G 1.06 7.01.26

493 method G 1.07 7.01.27

491 method J 0.69 7.01.28

501 method J 0.65 7.01.29

461 method J 0.60 7.01.30

490 method J 0.65 7.01.31

460 method L 0.70 7.01.32

479 method J 0.68 7.01.33

468 method J 0.67 7.01.34

439 method J 0.63 7.01.35

438 method J 0.65 7.01.36

469 method J 0.72

7.02.01. 2-[4-(4-Methoxy-phenyl)-2-phenyl-imidazol-1-yl]-1-(4-pyridin-2-yl-piperazin-1-yl)-ethanone

250 μl 1 mol/L lithium his (trimethylsilyl) amide solution in THF was added to 29 mg 2-bromo-1-(4-pyridin-2-yl-piperazin-1-yl)-ethanone in 1 mL DMF. The mixture was stirred 10 min at RT and 28 mg 4-(4-methoxy-phenyl)-2-phenyl-1H-imidazole was added. The reaction was stirred 2 h at 60° C. The mixture was purified by HPLC to give 30 mg desired product.

R_(t): 1.56 (method C), (M+H)⁺: 454

By using the same synthesis strategy as for 2-[4-(4-Methoxy-phenyl)-2-phenyl-imidazol-1-yl]-1-(4-pyridin-2-yl-piperazin-1-yl)-ethanone the following compounds were obtained:

MS HPLC Rt Examples Product m/z [M + H]⁺ Method min 7.02.02

439 method C 1.60 7.03.03

443 method C 1.57

7.03.01. 2-[4-(4-Fluoro-phenyl)-2-phenyl-imidazol-1-yl]-1-(4-pyrimidin-2-yl-piperazin-1-yl)-ethanone

43 mg 2-(4-bromo-2-phenyl-imidazol-1-yl)-1-(4-pyrimidin-2-yl-piperazin-1-yl)-ethanone in 1 mL dioxane and 500 μL methanol was added to 18 mg 4-fluorphenylboronic acid. Then 15 mg 1,1′-bis(diphenylphosphino) ferrocenedichloropalladium (II), and 100 μL 5 mol/L aqueous potassiumcarbonate solution was added to the mixture. The reaction was stirred 15 min at 140° C. and then filtered over basic Alox. The filtrate was purified by HPLC to give 29 mg desired product. R_(t): 1.67 (method K), (M+H)⁺: 443

By using the same synthesis strategy as for 2-[4-(4-Fluoro-phenyl)-2-phenyl-imidazol-1-yl]-1-(4-pyrimidin-2-yl-piperazin-1-yl)-ethanone the following compounds were obtained:

MS HPLC Rt Examples Product m/z [M + H]⁺ Method min 7.03.02

439 method K 1.70 7.03.03

473 method B 1.06 7.03.04

443 method K 1.68 7.03.05

477 method K 1.77 7.03.06

469 method K 1.71 7.03.07

471 method K 1.83 7.03.08

469 method K 1.70 7.03.09

473 method K 1.82 7.03.10

461 method K 1.70 7.03.11

496 method K 1.61 7.03.12

469 method K 1.74 7.03.13

459 method K 1.74 7.03.14

493 method K 1.80 7.03.15

481 method K 1.70 7.03.16

479 method K 1.51 7.03.17

473 method K 1.66 7.03.18

453 method K 1.79 

1. A compound of formula I

in which R¹ represents phenyl,

Ar represents

the group

represents

or a physiologically acceptable salt thereof.
 2. A compound selected from the group consisting of

or a physiologically acceptable salt thereof.
 3. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.
 4. A method of treating schizophrenia, schizoaffective disorder and substance induced psychotic disorder; cognitive disorders and dementias including age-associated learning and memory impairments or losses, post stroke dementia, deficits in concentration, mild cognitive impairment, the cognitive dysfunction in Alzheimers disease or the cognitive dysfunction of schizophrenia comprising administering to a patient a therapeutically effective amount of a compound according to claim
 1. 